Unexplained fever occurs commonly in certain malignant diseases, although the cause is unknown. In studies of experimental fever in animals, release of a small protein, endogenous pyrogen (EP), from several different cell types in response to microbial or antigenic stimuli has been implicated as the mechanism for temperature elevation. In the proposed research, studies are planned to investigate the mechanism of release of EP in vitro from cells and tissues from patients with malignant lymphoma, hypernephroma, and other malignancies. The cell types involved, the nature of effective stimuli, influence of environmental factors, and dynamics of production will be analyzed. The role of host immune responses in this process will be investigated by study of the influence of serum antibodies and of delayed hypersensitivity reactions of lymphocytes from these patients. Finally, the behavior of various normal, virus-infected, and malignant cell lines in tissue culture will be examined. Processes important for pyrogen production will be related to other metabolic and morphologic characteristics of these cells.